Clínicas de ketamina: usos actuales según la evidencia / Ketamine clinics: current uses based on evidence

Resumen: La ketamina es un medicamento conocido por sus bondades como inductor anestésico y para disminuir la posibilidad de complicaciones, por ejemplo, exacerbación del dolor neuropático e hiperalgesia asociada a opioides. En esta revisión nos enfocaremos en otras indicaciones en las que también ha demostrado ser útil y que, bajo observación e instrucción adecuadas en una infraestructura diseñada para ello (clínicas de ketamina), mejora la calidad en el comportamiento y disminuye el estrés, ansiedad y dolor. Entre las indicaciones para su uso se encuentran los trastornos depresivos, el trastorno de ansiedad, el trastorno obsesivo compulsivo y los relacionados con traumas emocionales; el trastorno bipolar, anormalidades en conducta e ingesta alimentaria, al igual que los trastornos adictivos.

Abstract: Ketamine is a drug known for its benefits as an anesthetic inducer and to reduce the possibility of complications such as exacerbation of neuropathic pain and hyperalgesia associated with opioids. In this review we will focus on other indications in which it has also proven to be useful and that, under adequate observation and instruction in an infrastructure designed for it (ketamine clinics), improves the quality of behavior and decreases stress, anxiety and pain. Among the indications for its use are depressive disorders, anxiety disorder, obsessive-compulsive disorder and those related to emotional trauma; bipolar disorder, abnormalities in behavior and eating intake as well as addictive disorders.

Anestesia intravenosa contínua com cetamina racêmica ou dextrocetamina e detomidina em cadelas / [Continuous intravenous anesthesia with racemic ketamine or dextroketamine and detomidine in female dogs]

Objetivou-se com este estudo comparar a associação de detomidina e cetamina ou dextrocetamina, por via intravenosa contínua, em oito cadelas submetidas a dois protocolos: GCD - indução anestésica com 5mg/kg e infusão intravenosa contínua de 20mg/kg/h de cetamina; e GDD - indução com 3,5mg/kg e infusão de 14mg/kg/h de dextrocetamina. Associou-se detomidina, 30µg/kg/h, em ambos os grupos. Registraram-se frequência cardíaca (FC), pressão arterial (PA), frequência respiratória (f), temperatura (TC), miorrelaxamento, analgesia, hemogasometria e eletrocardiograma, antes e 15 minutos após a MPA (Mbasal e Mmpa); após o início da infusão (Mic); a cada 10 minutos até 90 minutos (M10, M20, M30, M40, M50, M60, M70, M80 e M90); e 30 minutos após o fim da infusão (M120). Foi observada bradicardia em Mmpa no GCD e de Mmpa a M10 no GDD. Ocorreu hipotensão em Mmpa e hipertensão a partir de Mic. A f diminuiu de M10 a M30. Foram observados: onda T de alta amplitude, bloqueios atrioventriculares e parada sinusal. Ocorreu acidose respiratória. O período de recuperação foi de 219,6±72,3 minutos no GCD e de 234,1±96,8 minutos no GDD. A cetamina e a dextrocetamina, associadas à detomidina por infusão contínua, causam efeitos cardiorrespiratórios e anestésicos similares.(AU)

The combination of detomidine and ketamine or dextrocetamine for continuous intravenous infusion was compared in eight female dogs submitted to two protocols: GCD - 5mg/kg of anesthetic induction and continuous intravenous infusion of ketamine 20mg/kg/h; and GDD - induction with 3.5mg/kg and infusion of 14mg/kg/h of dextrocetamine. Detomidine, 30µg/kg/h was associated in both groups. Heart rate (HR), blood pressure (BP), respiratory rate (RR), temperature (CT), myorelaxation, analgesia, blood gas analysis and electrocardiogram were recorded before and 15 minutes after MPA (Mbasal and Mmpa); after the start of infusion (Mic); every 10 minutes to 90 minutes (M10, M20, M30, M40, M50, M60, M70, M80 and M90); and 30 minutes after the end of infusion (M120). Bradycardia was observed in Mmpa in GCD and from Mmpa to M10 in GDD. There was hypotension in Mmpa and hypertension from Mic. The RR decreased from M10 to M30. High amplitude T wave, atrioventricular blocks and sinus arrest were observed. Respiratory acidosis occurred. The recovery period was 219.6±72.3 minutes in GCD and 234.1±96.8 minutes in GDD. Ketamine and S+ ketamine associated with detomidine for continuous infusion cause cardiorespiratory and similar anesthetic effects.(AU)

Memantine for episodic migraine: A systematic review and meta-analysis

@#<p style="text-align: justify;"><strong>Introduction.</strong> Migraine is a common, debilitating primary headache. Memantine is a non-competitive N-methyl D-aspartate (NMDA) antagonist that lowers neuronal excitability that could prevent migraine attacks. This study aimed to determine the efficacy and safety of memantine in patients with episodic migraine attacks using a systematic review and meta-analysis.</p><p style="text-align: justify;"><strong>Methods.</strong> We searched CENTRAL, MEDLINE, Scopus, Cochrane, LILACS, ClinicalTrials.gov, HERDIN and Google Scholar for relevant studies until July 31, 2020. Prespecified screening and eligibility criteria for inclusion were applied. Included studies underwent methodological quality assessment. Study design, patient characteristics, interventions given, and relevant outcomes were extracted and synthesized.</p><p style="text-align: justify;"><strong>Results.</strong> This review included five relevant articles - two randomized controlled trials (RCT) and three non randomized studies (one retrospective records review and survey, two prospective open-label single-arm trials). There were 109 patients included in the RCTs and 197 patients reported in the non-randomized studies. Pooled data from the two RCTs showed that memantine at 10 mg/day significantly decreased the monthly number of migraine days at 12 weeks compared to placebo with a mean difference of -1.58 [95% confidence interval (CI) -1.84, -1.32]. Non-randomized studies also showed a decrease in migraine days per month with memantine (5 to 20 mg/day) after 12 weeks [95% CI]: -9.1 [-11, -7.23], -7.2 [-8.85, -5.55], and -4.9 [-6.29, -3.51]. Adverse drug events (ADE) did not differ significantly between patients treated with memantine compared to placebo.</p><p style="text-align: justify;"><strong>Conclusion.</strong> Memantine may be effective and well-tolerated as prophylaxis for episodic migraine.</p>

Differential Effects of Olanzapine and Haloperidol on MK-801-induced Memory Impairment in Mice

OBJECTIVE: We investigated the differential effects of the antipsychotic drugs olanzapine and haloperidol on MK-801-induced memory impairment and neurogenesis in mice. METHODS: MK-801 (0.1 mg/kg) was administered 20 minutes prior to behavioral testing over 9 days. Beginning on the sixth day of MK-801 treatment, either olanzapine (0.05 mg/kg) or haloperidol (0.05 mg/kg) was administered 40 minutes prior to MK-801 for the final 4 days. Spatial memory performance was measured using a Morris water maze (MWM) test for 9 days (four trials/day). Immunohistochemistry with bromodeoxyuridine (BrdU) was used to identify newborn cells labeled in tissue sections from the dentate gyrus of the hippocampus. RESULTS: MK-801 administration over 9 days significantly impaired memory performance in the MWM test compared to untreated controls (p<0.05) and these deficits were blocked by treatment with olanzapine (p<0.05) but not haloperidol. The administration of MK-801 also resulted in a decrease in the number of BrdU-labeled cells in the dentate gyrus (28.6%; p<0.01), which was prevented by treatment with olanzapine (p<0.05) but not haloperidol. CONCLUSION: These results suggest that olanzapine has a protective effect against cognitive impairments induced by MK-801 in mice via the stimulating effects of neurogenesis.

Dissociated Antidepressant and Analgesic Effects of Intravenous Ketamine in Patients with Chronic Pain / 대한정신약물학회지

OBJECTIVE: Recent studies about low-dose ketamine therapy have found significant improvement of depressive symptoms within a few hours or days. This study was designed to investigate the effect of ketamine on mood in patients with chronic pain. METHODS: Forty subjects with chronic pain were recruited from the pain clinic of the Ajou University Hospital. The Beck Depression Inventory was used to evaluate mood in each patient, and then the patients received ketamine hydrochloride (1.2 mg/kg, average) intravenously over the course of 1 hour. Visual Analogue Scale (VAS) for depression, anxiety, and pain were completed by the subjects just before and 3 hours after ketamine infusion. RESULTS: VAS scores for depression, anxiety, and pain were significantly decreased after ketamine infusion. VAS for depression, anxiety, and pain showed significant correlation with each other before ketamine infusion; however, correlations of the VAS scores for pain with the other two visual scale measures were absent at post-ketamine administration while the correlation between depression and anxiety following ketamine infusion was maintained. CONCLUSION: To our knowledge, this is the first report about the antidepressant effect of intravenous ketamine, which is separated from its analgesic effect in patients with chronic pain. This result raises the possibility that the antidepressant effect of ketamine is generated by a mechanism different from that of the analgesic effect in human.

Ketamina, una antigua droga que renace ante el dolor: Parte II / Ketamine, an old drug coming back for pain management: Part II

Esta segunda parte trata el tema de la hiperalgesia, siguiendo el modelo de la hiperalgesia postoperatoria. Se sabe que a pesar del conocimiento de la neurofisiología del dolor, sigue teniendo una alta incidencia de dolor postoperatorio, dolor crónico postoperatorio y dolor crónico postraumático. En todas estas situaciones, la nocicepción del dolor está aumentada, dada principalmente por la presencia de hiperalgesia. Se sabe que su diagnóstico es difícil, pero es necesario sospecharla para tratarla precozmente y evitar las repercusiones negativas en el individuo. En la hiperalgesia existe activación de los receptores NMDA,se postula que al ser bloqueado por la ketamina, principal antagonista de estos receptores, se tendría menor hiperalgesia y, por ende, menor dolor.

This second part addresses hyperalgesia following the postoperative hyperalgesia model. It is well known that in spite of the wide knowledge regarding pain neurophysiology, it still has a great impact on postoperative pain, postoperative chronic pain and post traumatic chronic pain. In all those situations, pain nociception is increased mainly due to the presence of hyperalgesia. Diagnosing it is difficult, however, one should suspect it so to start treatment at an early stage and avoid negative consequences for patients. Hyperalgesia is present in NMDA receivers which, as some think, if blocked by Ketamine, the main antagonist of these receivers, hyperalgesia will be lessened, hence pain reduced.

Analgesia em procedimentos cirúrgicos de abdômen superior com bloqueio interpleural / Analgesia in upper abdominal surgery with interpleural block

JUSTIFICATIVA E OBJETIVOS: Pesquisas empregando bloqueio interpleural com anestésico local, opioide e agonista Alfa2-adrenérgico ou bloqueador do receptor N-metil-D-aspartato (NMDA), observaram a ocorrência de analgesia pós-operatória em cirurgias de abdômen superior. O objetivo deste estudo foi observar a presença de dor no pós-operatório de cirurgias de colecistectomia por via subcostal.MÉTODO: Após aprovação pelo Comitê de Ética, participaram do experimento aleatório e prospectivo, 40 pacientes, de ambos os sexos, com idade variando de 18 a 50 anos, peso entre 50 e 100 kg, estado físico ASA I e II, submetidos à colecistectomia por via subcostal, sob anestesia geral associada ao bloqueio interpleural. Foram administradas levobupivacaína a 0,5% (100 mg) com adrenalina 1:200.000 (5 µg.mL-1) ou ropivacaína a 0,75% (150 mg), morfina (3 mg) e clonidina (3 µg.kg-1) ou cetamina (0,5 mg.kg-1), ao nível EIC7, na linha axilar média, com agulha de Tuohy 17G, por via interpleural. A indução da anestesia geral foi realizada com a injeção de etomidato (0,2 mg.kg-1), alfentanil (30 µg.kg-1) e rocurônio (0,6 mg.kg-1) e a manutenção com oxigênio e isoflurano (0,5 vol% a 3,0 vol%). A analgesia pós-operatória, analisada pela escala analógica visual (EAV), foi observada às 6h, 12h, 18h e 24h após o término do ato operatório.RESULTADOS: Apresentaram dor pós-operatória: grupo RMC (ropivacaína, morfina e clonidina), um até 6h, seis entre 6 e 12h e um entre 18 e 24h; grupo RMK (ropivacaína, morfina e cetamina), quatro até 6h, quatro entre 6 e 12h, um entre 12 e 18h e um entre 18 e 24h; grupo LMC (levobupivacaína, morfina e clonidina), quatro até 6h e quatro entre 6 e 12h; grupo LMK (levobupivacaína, morfina e cetamina, cinco até 6h, quatro entre 6 e 12h e um entre 12 e 18h. Aplicando o teste Exato de Fisher observou-se diferença estatística significante entre o tempo de observação até 6h e os demais no grupo RMC; entre o tempo de observação até 6h e os 12-18h e 18-24h nos grupos RMK e LMK. Não ocorreram complicações relacionadas ao bloqueio interpleural.CONCLUSÃO: A necessidade de associar opioide ao analgésico comum para abolir a dor, em cirurgias de colecistectomia por via subcostal, ocorreu em número reduzido de pacientes.

BACKGROUND AND OBJECTIVES: Researches using interpleural block with local anesthetics, opioid and alpha2-adrenergic agonist or N-Methyl-D-aspartate (NMDA) receptor blocker have shown the presence of postoperative analgesia in upper abdominal surgeries. This study aimed at observing the presence of pain in the postoperative period of subcostal cholecystectomies. METHOD: After The Ethics Committee approval, participated in this randomized, prospective study 40 patients of both genders, aged 18 to 50 years, weighing between 50 and 100 kg, physical status ASA I and II, submitted to subcostal cholecystectomy under general anesthesia associated to interpleural block. The following drugs were administered: 0.5% levobupivacaine (100 mg) with 1:200.000 epinephrine (5 µg.mL-1) or 0.75% ropivacaine (150 mg), morphine (3 mg) and clonidine (3 µg.kg-1) or ketamine (0,5 mg.kg-1), at EIC7, in the medium axillary line with 17G Tuohy needle by interpleural route. General anesthesia was induced with etomidate (0.2 mg.kg-1), alfentanil (30 µg.kg-1) and rocuronium (0.6 mg.kg-1) and was maintained with oxygen and isoflurane (0.5 vol% at 3.0 vol%). Postoperative analgesia, evaluated by the visual analog scale (VAS), was observed at 6h, 12h, 18h and 24h after surgery completion.RESULTS: Postoperative pain was observed: one patient up to 6h, six between 6 and 12h and one between 18 and 24h in the RMC group (ropivacaine, morphine and clonidine); four patients up to 6h, four between 6 and 12h, one between 12 and 18h and one between 18 and 24h in the RMK group (ropivacaine, morphine and ketamine); four patients up to 6h, and four between 6 and 12h in the LMC group (levobupivacaine, morphine and clonidine); five patients up to 6h, four between 6 and 12h, and one between 12 and 18h in the LMK group (levobupivacaine, morphine and ketamine). Fisher's Exact test has shown statistically significant difference between 6h observation time and the others in the RMC group; between 6h observation time and 12-18h and 18-24h in RMK and LMK groups. There were no interpleural block-related complications.CONCLUSION: Only a small number of patients needed the association of opioid to normal analgesics to abolish pain in subcostal cholecystectomy surgeries.

Ketamina, una antigua droga que renace ante el dolor: parte I / Ketamine, and old drug coming back for pain management: part I

La Ketamina es una antigua droga usada como inductor anestésico, que debido a sus efectos adversos alucinatorios se subutilizó en las últimas décadas, pero debido al avance de las neurociencias y al conocimiento del dolor, renace como un potente medicamento analgésico (antihiperalgésico). Es un bloqueador no competitivo de los receptores NMDA, que son los receptores que se activan cuando el dolor es intenso, se postula que se podría utilizar para disminuir la percepción del dolor. es un neuromodulador del dolor y potenciador de la acción analgésica de los opioides. Los estudios clínicos han evidenciado su uso en el manejo del dolor postoperatorio dentro de una modalidad multimodal, con menor incidencia de náuseas y vómitos que al usar opioides solos y con reacciones adversas de tipo alucinatorias escasas. Las dosis ideales para los distintos tipos de cirugía, actualmente se basan en opiniones de expertos y se requieren mayores estudios. En dolor neuropático y en dolor por cáncer existe evidencia tipo IV, basadas en serie de casos que muestra ser útil. En tolerancia por opioides y en cronificación del dolor postoperatorio existen buenos estudios, pero aún no concluyentes. En conclusión, la ketamina es un fármaco útil, pero se debe conocer muy bien su farmacología para poder usarlo de manera segura y con un buen criterio clínico para el manejo del dolor moderado y/o intenso.

Ketamine is an old drug used in the induction of anesthesia that due to adverse hallucinatory effects has been under utilized during the past decades. However, the advances in neuroscience and a deeper knowledge of pain, ketamine is reborn as a strong analgesic (antihyperalgesic) aid. Ketamine is a non competitive blocker of NMDA receptors that are activated by severe pain and it could be used in pain reduction. Ketamine is a pain neuromodulator and enhancer of the opioids analgesic action. Clinicals trials showed it can be used in post surgery pain management in a number of ways with lessened side effects sunch as nausea and vomiting and scare hallucinatory effects compared to those caused by opioid treatment alone. the ideal dosage for different types of surgery now relies on the opinion of experts, however, further research is required. In neuropathic and cancer pain there is type IV evidence based on a number of cases that proves to be useful. Good trials, but not yet conclusive have been made in matters of tolerance to opioids and post surgery chronic pain. In conclusion, Ketamine is a useful drug, however, a deep knowledge of the same as well as good judgement are required for using it in moderate and/or severe pain management.

MRI Structure and Histological Change of Rat after Memantine Intake in Olfactory Bulbectomised Depression Model / 대한정신약물학회지

OBJECTIVE: The validity of olfactory bulbectomized rat as an animal depression model and the possibilities of the NMDA antagonist as an antidepressant would be evaluated by demonstrating structural alterations in their brain MRIs and histological findings of hippocampus. METHODS: Those 8-week old male Sprague-Dawley rats received either an olfactory bulbectomy or sham operation and volume changes at ventricles and caudate nucleus in their brain MRI were acquired at preoperation and postoperation. Those olfactory bulbectomized rats received either memantine, an uncompetitive NMDA antagonist, or normal saline, a placebo, and their brain structural changes in MRI were acquired. At preoperation, postoperation, and postmedication each one of the rats with sham-operation, with memantine, and with placebo was sacrificed to acquire histological impressions. RESULTS: 1) Comparison of the volume changes between preoperation and postoperation showed statistical significance; the volumes of the left and right lateral ventricles (p=0.007, p=0.008) and the third ventricle (p=0.003) increased significantly but the volumes of left and right caudate nucleus decreased (p=0.014, p=0.032), compared to that of the controls. 2) After 6-weeks of memantine administrations, the OB rats revealed more definite recovery in brain MRIs statistically than the controls: the volumes of left and right ventricles and left and right caudate nucleus (p=0.004, p=0.03 ; p=0.04, p=0.05). 3) The hippocampus histological findings of the olfactory bulbectomy showed frequently eosinophilic cytoplasm and hyperchromatic nucleus with shrinkage in CA3. After memantine intake, the hippocampus histological findings returned to nearly normal and showed mixtures of normal cell and abnormal neuron cell. CONCLUSION: The OB models would be valid as an animal model of depression and alterations in their brain MRI images after administrations of NMDA antagonist could be an indicator of antidepressant effects.

Amantadine as Treatment for Levodopa-Induced Dyskinesia

BACKGROUND: Dyskinesia is a common side effect complicating long-term levodopa therapy for Parkinson's disease. However, the pathogenesis of dyskinesia has not been completely understood. In recent animal studies, it has been reported that a NMDA (N-methyl-D-aspartate) antagonist reduced levodopa-induced dyskinesia. These findings suggest that the hyperfunction of NMDA receptors on striatal efferent neurons contributed to the pathogenesis of dyskinesia. Amantadine has also been recently shown to antagonize central NMDA receptors. In the present study, we observed amantadine efficacy in levodopa-induced dyskinesia in parkinsonian patients. METHODS:Twenty-two parkinsonian patients with levodopa-induced dyskinesia participated in a placebo-controlled, cross-over study. We prescribed 100 mg amantadine daily as a starting dose, which was built up every four days and titrated up to 400 mg a day. After two weeks of a wash-out period, a placebo was given with the same schedule. The doses of levodopa and other antiparkinsonian drugs were unchanged during this period. We assessed the duration and disability of dyskinesia (UPDRS part IV, item 32 and 33) based on diary and interview. RESULTS: Amantadine was superior to placebo in reducing the duration of dyskinesia in 9 patients (42.9%) and the disability of dyskinesia in 11 patients (52.4%). The reduction of the duration and disability of dyskinesia was correlated with the dose of amantadine. CONCLUSIONS These findings suggest that amantadine can improve levodopa induced dyskinesia and supports the view that the hyperfunction of NMDA receptors contributes to the pathogenesis of levodopa induced dyskinesia.

Influence of Brain Edema on the Antiischemic Effect of D-CPPene in Rat Focal Cerebral Infarction

OBJECTIVE: The model of focal ischemia that involves occlusion of middle cerebral artery(MCA) is one of the most commonly used methods in the rat, which can be considered to be equivalent to a focal cerebral infarction in man. Infarction size is often used as the standard to assess potential therapeutic regimens in models of focal cerebral infarction. In practice, scientists have estimated infarction volume by a variety of methods. One of the fundamental problems in measuring infarction volume is the enlargement of infarcted tissue by edema. To minimize the error of overestimation that may be caused by edema, several methods have been proposed. METHOD:The author assessed the antiischemic effect of a competitive N-methyl-D-aspartate(NMDA) antagonist, D-(E)-4-(3-phosphonoprop-2-enyl) piperazine-2carboxylic acid(D-CPPene) in MCA occlusion model in the rat. Four different morphometric analysis were used to measure infarction volume a real measurement, the Swanson's method designed to minimize the error of overestimation, a measurement using a diagram, percentage method (infarction volume divided by the volume of ipsilateral hemisphere), which were to elucidate the effects of each method upon measuring the infarction volume regarding the possible influence of edema. The animals were sacrificed 24 hours after MCA occlusion and the amount of ischemic brain damage was assessed by 8 predetermined coronal planes. RESULT: Post-occlusion treatment of D-CPPene which was initiated 15 minutes after MCA occlusion, produced reduction of infarction volume to about 40% compared to the control(p<0.05). The volume of infarction determined by a real measurement was much larger than that by the Swanson's or diagram method(p<0.05), about 70% larger in the control and 2 times larger in the treated group. However, there was no significant difference in the measured volume between the Swanson's and diagram methods. The protection rate which was obtained by subtracting the infarction volume of the treated from that of the control, was larger by the Swanson's and diagram method than by a real measurement and percentage method. CONCLUSION: These results demonstrate that a competitive NMDA antagonist, D-CPPene which was administered 15 minutes after post-occlusion, has a significant neuroprotective effect on ischemic brain damage in focal cerebral infarction. But it appears to have no specific protective effect on ischemic brain edema. The overestimation of infarction volume at the peak time of brain edema could be substantially reduced by not only the Swanson's method but also the diagram method.

Effect of MK-801 on Neuronal Cell Loss and Fos Expression of Hippocampus in Lithium-Pilocarpine Induced Status Epilepticus / 대한간질학회지

BACKGROUND & OBJECTIVES: Endogenous excitatory amino acid has been implicated in neuronal damages occurred neurotransmitter in the CNS, Exerts its neurotoxic activity primarily by binding to the NMDA receptor, one of the three glutamate receptors, We evaluated the effect of MK-801, a non-competitive NMDA receptor antagonist, on both Fos expression and neuronal damages in lithium-pilocarpine induced status epilepticus rat model. METHODS: Seizured was induced in rats by lithum pretreatment followed by low dose of pilocarpine (30 mg/kg, ip). MK-801 (1 mg/kg) was treated 15 min before (MK-801 Pre group, N=5) or 20 min after the injection of pilocarpine (MK-801 Post group, N-5). Saline, instead of MK-801, was injected for the Control group (N=5). RESULTS: Seizure-induced neuronal damages, which was evaluated by the counting of the number of viable pyramidal cells in the area of CA1 and CA3 of the hippocampus, were significantly inhibited by MK-801 in both MK-801 Pre and Post groups. This protective effect of MK-801 was observed only in the CA1 area and was not typical in the CA3 area in both groups, and there was no differences in MK-801 activity between Pre and Post group. We also examined the expression of Fos, which has been known to be involved in long-term neuronal plasticty or delayed neuronal insults, by the immunohistochemical analysis in the hippocampus and thalamus. Pilocarpine induced Fos expression significantly in the Control group and moderately in the MK-801 Post groups, whereas, it was completely blocked by the pretreatment of MK-801 in hippocampus. CONCLUSION: Our results showed that MK-801 prevented the hippicampal cells from neuronal damages as well as inhibited Fos expression in the pilocarpine-induced rat seizure models. These results suggest the roles of NMDA receptor and Fos protein in seizure-related hippicampal damages.